Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor–Biased Ligand in Adults With COVID-19

• DOI: 10.1001/jama.2023.3546
• Publication Date: 2023-04-11T15:04:43Z
• Authors: Wesley H. Self; Matthew S. Shotwell; Kevin W. Gibbs; Marjolein de Wit; D. Clark Files; Michelle Harkins; Kristin M. Hudock; Lisa H. Merck; Ari Moskowitz; Krystle D. Apodaca; Aaron Barksdale; Basmah Safdar; Ali Javaheri; Jeffrey M. Sturek; Harry Schrager; Nicole Iovine; Brian Tiffany; Ivor S. Douglas; Joseph Levitt; Laurence W. Busse; Adit A. Ginde; Samuel M. Brown; David N. Hager; Katherine Boyle; Abhijit Duggal; Akram Khan; Michael Lanspa; Peter Chen; Michael Puskarich; Derek Vonderhaar; Lokesh Venkateshaiah; Nina Gentile; Yves Rosenberg; James Troendle; Amanda J. Bistran...; Josh DeClercq; Robert Lavieri; Meghan Morrison Joly; Michael Orr; Jill Pulley; Todd W. Rice; Jonathan S. Schil...; Matthew W. Semler; Li Wang; Gordon R. Bernard; Sean P. Collins; ; Richard C. Becker; Gregory del Zoppo; Peter Henke; Richard Holubkov; Maryl Johnson; Kim Kerr; Hannah I. Lipman; Fedor Lurie; Bertram Pitt; Sara K. Vesely; Jerome L. Fleg; Dave Aamodt; J'Mario Ayers; Debra Clark; Jessica Collins; Maya Cook; Sheri Dixon; John Graves; Courtney Jordan; Christopher J. Li...; Itzel Lopez; David McKeel; Dirk Orozco; Nelson Prato; Ally Qi; Madiha Qutab; Christa Stoughton; Krista Vermillion; Kelly Walsh; Stephanie Winchell; Taylor Young; Richard Franklin; Elizabeth Wagner; Thomas Walther; Mark Demitrack; Jakea Johnson; Ryan Walsh; Brian Bales; Karen Miller; Donna Torr; Harsh Barot; Leigha Landreth; Mary LaRose; Lisa Parks; J. Pedro Teixeira; Sandra Cardenas; Juan A. Ceniceros; Amy G. Cunningham; Susan Kunkel; Debbie M. Lovato; Brooklin Zimmerman; Thanh Nguyen; Wesley Zeger; Heather Nichols; Noah Wiedel; Ali Javaheri; Stephanie Stilinovic; Carolyn Brokowski; Jing Lu; Muriel Solberg; Dana Lee; Kristopher Roach; Brian Tiffany; Charlotte Tanner; Annette Taylor; Jennine Zumbahl; Aamer Syed; Jessica Mason; Patrick E. H. Jac...; Rachael W. Coleman; Heather M. Haughey; Kartik Cherabuddi; Nastasia James; Rebecca Wakeman; Christopher Duncan; Cynthia Montero; Angela J. Rogers; Jennifer G. Wilson; Rosemary Vojnik; Cynthia Perez; David Wyles; Terra D. Hiller; Judy L. Oakes; Ana Z. Garcia; Michelle Gong; Amira Mohamed; Luke Andrea; Rahul Nair; William Nkemdirim; Brenda Lopez; Sabah Boujid; Martha Torres; Ofelia Garcia; Flora Martinez; Amiran Baduashvili; Jill Bastman; Lakshmi Chauhan; David J. Douin; Lani Finck; Ashley Licursi; Caitlin ten Lohuis; Sophia Zhang; William Bender; Santiago Tovar; Sharon Hayes; Nicholas Kurtzman; Elinita Rosseto; Douglas Scaffidi; Nathan Shapiro; Jonathan Pak; Gopal Allada; Genesis Briceno; Jose Peña; Minn Oh; Harith Ali; Sasha Beselman; Yolanda Eby; Vitaliy Klimov; R. Duncan Hite; Hammad Tanzeem; Chris Droege; Jessica Winter; Susan Jackman; Antonina Caudill; Emad Bayoumi; Ethan Pascual; Po-En Chen; Simon Mucha; Nirosshan Thiruch...; Matthew Siuba; Omar Mehkri; Brian E. Driver; Audrey F. Hendric...; Olivia R. Kaus; Christina Ontiveros; Amy Riehm; Sylvia Laudun; Debra Hudock; Christopher Ensley; Valerie Shaner; Nina Gentile; Derek Isenberg; Hannah Reimer; Paul Cincola; Estelle S. Harris; Sean J. Callahan; Misty B. Yamane; Macy AG Barrios; Neeraj Desai; Amit Bharara; Michael Keller; Prat Majumder; Carrie Dohe; Jeanine D’Armiento; Monica Goldklang; Gebhard Wagener; Laura Fonseca; Itzel Valezquez-S...; Nicholas J. Johnson; Emily Petersen; Megan Fuentes; Maranda Newton; Stephanie Gundel; Vasisht Srinivasan; Tessa Steel; Bryce Robinson
• Keywords: Adult; Male; Angiotensins; SARS-CoV-2; Angiotensin II; Vasodilator Agents; COVID-19; Middle Aged; Ligands; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; 03 medical and health sciences; 0302 clinical medicine; Humans; Female; Hypoxia; Infusions, Intravenous; Oligopeptides; Randomized Controlled Trials as Topic

Importance Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase relative activity angiotensin II compared with (1-7) and be an important contributor to COVID-19 pathophysiology. Objective To evaluate efficacy safety RAS modulation using 2 investigational agents, TXA-127 (synthetic [1-7]) TRV-027 (an type 1 receptor–biased ligand), that are hypothesized potentiate action mitigate II. Design, Setting, Participants Two randomized clinical trials including adults hospitalized acute new-onset hypoxemia were conducted at 35 sites in US between July 22, 2021, April 20, 2022; last follow-up visit: 26, 2022. Interventions A 0.5-mg/kg intravenous infusion once daily for 5 days or placebo. 12-mg/h continuous Main Outcomes Measures The primary outcome was oxygen-free days, ordinal classifies a patient’s status day 28 based on mortality duration supplemental oxygen use; adjusted odds ratio (OR) greater than 1.0 indicated superiority agent vs key secondary 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, hypotension. Results Both met prespecified early stopping criteria low probability efficacy. Of 343 patients trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, 274 [79.9%] not Hispanic), 170 received 173 290 (199 [68.6%] 168 [57.9%] 195 [67.2%] [77.6%] 145 Compared placebo, both (unadjusted mean difference, −2.3 [95% CrI, −4.8 0.2]; OR, 0.88 0.59 1.30]) −2.4 −5.1 0.3]; 0.74 0.48 1.13]) resulted no difference days. In trial, occurred 22 163 (13.5%) group 166 (13.3%) placebo (adjusted 0.83 0.41 1.66]). 29 141 (20.6%) 18 140 (12.9%) 1.52 0.75 3.08]). frequency similar either Conclusions Relevance severe COVID-19, (TXA-127 TRV-027) did improve These results do support hypotheses pharmacological interventions selectively block receptor COVID-19. Trial Registration ClinicalTrials.gov Identifier: NCT04924660